1 . Field of the Invention
The present invention relates to pharmaceutical compositions. In particular, this invention relates to ophthalmic compositions and drug delivery vehicles which are administrable as liquids and which gel upon contact with the eye.
2. Description of Related Art
Although gels are desirable because they prolong the contact or residence time of drugs in the eye, they are not as easy to administer topically as liquid drops. A variety of gelling drug delivery systems have been developed in an effort to allow an ophthalmic pharmaceutical composition to be topically administered as a liquid drop and then gel upon contact with the eye. Drug delivery vehicles containing polysaccharide polymers which gel in response to a pH change have been proposed, such as those described in U.S. Pat. Nos. 4,136,173, 4,136,177, and 4,136,178, for example.
Drug delivery systems which gel in response to temperature changes have also been proposed. For example, drug delivery systems utilizing Tetronic.RTM., Pluronic.RTM., or other polyols have been disclosed in U.S. Pat. Nos. 4,474,751; 4,474,752; and 4,188,373. U.S. Pat. Nos. 5,124,151; 5,306,501 and 5,618,800 also disclose thermally gelling systems.
Alternatively, ion-sensitive gelling polymers have been identified. European Patent No. 0 227 494 B1 discloses ophthalmic compositions containing polysaccharides of the type that undergo liquid-gel phase transition under the effect of an increase in ionic strength. The only representative polysaccharide specifically disclosed by this European patent, however, is gellan gum. U.S. Pat. No. 5,403,841 discloses gelling ophthalmic compositions that contain carrageenans, such as Eucheuma Carrageenani. The carrageenan-containing compositions are characterized as capable of gelling in about 0.5 to 1% aqueous NaCl.
International Publication No. WO 92/09307 discloses gelable carrier compositions containing a water-soluble, nonionic cellulose ether polysaccharide, such as ethylhydroxyethylcellulose, and a charged surfactant. The reference compositions gel due to strong hydrophobic interactions between the polymer and the charged surfactant.
Various drug delivery systems employing combinations of two types of gelling polymers have also been disclosed. U.S. Pat. No. 5,077,033 discloses a thermally irreversible gel system comprising a combination of polyoxyalkylene and ionic polysaccharides. U.S. Pat. No. 5,296,228 discloses aqueous reversibly gelling polymeric solutions containing ion exchange resin particles. The polymeric component of the solution may be a pH sensitive polymer, a temperature sensitive polymer, or combinations of both pH-sensitive polymers and temperature sensitive polymers. U.S. Pat. No. 5,252,318 also discloses reversibly gelling aqueous compositions containing combinations of polymers, in this case at least one pH-sensitive reversibly gelling polymer and at least one temperature sensitive reversibly gelling polymer.
U.S. Pat. No. 5,212,162 discloses ophthalmic compositions containing gelling polysaccharides and drug carrier substrates. As used in the '162 patent, gelling polysaccharide means a polysaccharide capable of reversible liquid-to-gel transition based on a change in ionic strength or pH. According to the '162 patent, suitable gelling polysaccharides include xanthan gum, locust bean gum, gellan gum, carrageenans and combinations thereof. The '162 patent references U.S. Pat. Nos. 4,136,173, 4,136,177, and 4,136,178 in connection with xanthan gum and locust bean gum.
EP 0 424 043 A1 discloses liquid ophthalmic compositions that undergo liquid-gel phase transition upon administration to the eye. The compositions comprise an aqueous solution of at least one active agent and are characterized in that they contain 0.1 to 5% by weight of a sulfated polysaccharide derivative, preferably selected from kappa-carrageenan, iota-carrageenan and mixtures thereof, whereby the liquid-gel phase transition is mediated by interaction of the sulfated polysaccharide derivative with the proteins of the lachrymal fluid.
Xanthan gum is a polysaccharide known to be useful in ophthalmic compositions as a viscosity enhancing agent. U.S. Pat. No. 4,136,177 discloses ophthalmic compositions containing an ophthalmic drug and from about 0.01 to 2.5% (w/v) of xanthan gum. The '177 patent teaches that if the concentration of xanthan gum is from about 0.02 to about 1.0% (w/v), the composition is suitable for "dropwise" ophthalmic applications. In contrast, at concentrations of xanthan gum above about 1.0% and up to about 2.5% (w/v), "a gel-like consistency is attained." Thus, the '177 patent discloses compositions that are formulated to be either non-gelled liquids or gels before instillation in the eye. The '177 patent does not describe any xanthan gum-containing compositions as capable of being administered as a liquid and gelling upon contact with the eye.
U.S. Pat. No. 4,136,173 discloses ophthalmic compositions containing a combination of xanthan gum and locust bean gum. These compositions gel due to a change in pH. The '173 patent discloses that, in solutions containing either of these two gums alone, "sufficient gelling did not occur, nor, at the same time, did these solutions demonstrate pH sensitive liquid-gel reversibility." ('173 patent, Col. 4, lines 1-4).
It has been accepted in the art that xanthan gum is not a polymer of the type which is capable of undergoing a liquid-gel phase transition upon contact with the eye. See, for example, Meseguer, et al., Journal of Ocular Pharmacology and Therapeutics, 12(4):481-487 (1996), describing gellan gum as a "phase-transition system" but xanthan gum as a "viscosity enhancer."